TDP-43 was recently identified as one of the major proteins that accumulate in inclusions in Amyotrophic Lateral Sclerosis (ALS) and in Fronto-temporal lobar dementia with ubiquitin inclusions (FTLD-U). Abnormalities in TDP-43 biology appear to be sufficient to cause neurodegenerative disease because mutations in TDP-43 occur in familial ALS. The prevalence of TDP-43 deposits in diseases such as ALS and FTLD-U, combined with the ability of abnormal TDP-43 to cause disease places TDP-43 in the class of proteins that are major components of neurodegenerative disease. This class includes tau, α-synuclein, huntingtin and β-amyloid. Analysis of the biology of the major proteins that accumulate in other neurodegenerative diseases has lead to major advances in our understanding of the pathophysiology of the disease and also development of new drug discovery platforms. During the course of studying TDP-43, we discovered that this protein is part of the stress granule machinery. This work lead us to important discoveries about how to model the pathophysiology of ALS and FTLD-U in cell culture.
Currently, it is believed that aggregates that accumulate in neurodegenerative diseases like ALS, FTLD-U, Parkinson's disease and Huntington's disease accumulate slowly and are very difficult to disaggregate or perhaps can't be disaggregated. Thus, there is a need in the art for compostions and methods that can rapidly disaggregate stress granules and/or inhibit the formation of stress granules.